The goal of this proposal is to characterize a unique population of glial cells in the central nervous system (CNS) that can be identified by antibodies to NG2 proteoglycan and the alpha receptor for platelet- derived growth factor (PDGF). in vitro the two molecules are expressed o the surface of oligodendrocyte progenitor cells but are downregulated as they differentiate into mature oligodendrocytes. The presence of a physical interaction between NG2 and PDGF a receptor has been demonstrated by bioclleluical rllelhoils. Furthermore, incubation of oligodendrocyte progenitor cells with antibody to NG2 diminishes their ability to proliferate in response to PDGF. In the developing rat brain in vivo NG2 and PDGF a receptor are co- expressed on process-bearing cells that begin to appear during late embryonic stages and continue to increase in density through the first postnatal week. Our preliminary results indicate that the antibodies to the two molecules label a large population of process-bearing glial cells in the gray and white matter of the mature rat brain which appears to be distinct from microglia, mature oligodendrocyte, or mature astrocytes that express glial fibrillary acidic protein (GFAP). The specific aims of this proposal are designed to address the following questions: 1. Are the NG2=/PDGF ct receptor (N+P+) cells oligodendrocyte progenitor cells? (specific aim 1) 2. How do these cells respond to pathological conditions of white matter? (specific aim 2) and 3. what are the functions of N+P+ cells in gray matter? (specific aim 3). In specific aim la, the relationship between N+P+ cells and oligodendrocytes will be investigated by examining the changes in N+P+ cells in the dysmyelinating mutant jimpv, the phenotype of which is characterized by oligodendrocyte, death and increased proliferation of immature oligodendrocytes. In specific aim 1 b, immunopurified NG2+ cells carrying a genetic marker will be transplanted into the brain to determine whether they differentiate into oligodendrocytes and/or atrocytes in white and gray matter. In specific aim 2a, changes in N+P+ cells will be examined in the chronic relapsing mouse model of experimental autoimmune encephalomyelitis in order to determine whether N+P+ cells proliferate and differentiate into oligodendrocytes in response to myelin damage. The possibility that N+P+ cells interact with microglia will be investigated in vitro in specific aim 2b. In specific aim 3, a lcinic acid-induced gray matter lesion will be used to determine whether N+P+ cells in the gray matter can be induced to become GFAP-positive astrocytes. The possibility that N+P+ cells promote neuronal survival will be tested in vitro in specific aim 3b. These studies will enhance our current knowledge of glial cells and may have important clinical implications in devising strategies to promote remyelination in demyelinating diseases.